Pharmacokinetics, pharmacodynamics, and safety of verinurad with and without allopurinol in healthy Asian, Chinese, and non‐Asian participants

Abstract Verinurad is a selective inhibitor of uric acid transporter 1 (URAT1). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of verinurad + allopurinol and verinurad monotherapy in healthy participants. Studies 1 (NCT03836599) and 2 (NCT02608710) were randomized Phase 1 studies. In Study 1, 12 healthy Asian participants received 24 mg verinurad + 300 mg allopurinol or placebo, and 9 healthy Chinese participants received 12 mg verinurad + 300 mg allopurinol. In Study 2, 24 healthy non‐Asian male participants received 12 mg verinurad. Safety analyses included assessment of adverse events (AEs). Pharmacokinetic parameters included maximum concentration (Cmax) and area under plasma concentration‐time curve (AUC) over 24 h (AUCτ). Pharmacodynamic parameters included percentage change from baseline (day –1) in serum uric acid (sUA) and urinary uric acid (uUA). There were no serious AEs or deaths in either study. In Study 1, steady‐state geometric mean (gCV%) Cmax and AUCτ values of verinurad after 7 days’ dosing were 73.6 (29.0) ng/mL and 478 (18.4) ng·h/mL, respectively, in healthy Asian participants, and 42.0 (40.1) ng/mL and 264 (36.1) ng·h/mL, respectively, in healthy Chinese participants; in Study 2, gCV% values were 36.3 (36.5) ng/mL and 271 (31.0) ng·h/mL, respectively. sUA decreased and uUA excretion increased compared with baseline following verinurad + allopurinol (Study 1) or verinurad (Study 2). When accounting for dose, the steady‐state pharmacokinetics of verinurad following multiple dosing were comparable between healthy Asian and Chinese participants and healthy non‐Asian participants. Verinurad treatments were well tolerated, including at higher verinurad exposures than previously evaluated after repeated dosing.


| INTRODUC TI ON
High levels of serum uric acid (sUA) are observed in chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF) and may constitute either a contributing cause or risk factor for the diseases. [1][2][3][4] Consistent associations between sUA and CKD development and rapid progression [5][6][7][8] challenge the concept that increased sUA in patients with CKD should be viewed solely as a biomarker of decreased renal uric acid (UA) excretion. In HFpEF, an association between hyperuricemia and clinical outcomes, including all-cause hospitalization, has also been reported. 1,2 Currently available therapies for the correction of sUA in hyperuricemia include xanthine oxidase inhibitors (XOI) such as allopurinol and febuxostat, which inhibit UA production, and UA transporter 1 (URAT1) inhibitors such as probenecid, benzbromarone, and lesinurad, which decrease sUA levels by inhibiting its reabsorption and increasing renal excretion of UA. [9][10][11] Verinurad is a novel, selective, highly potent inhibitor of URAT1, 12 which is in development for CKD and HFpEF. Verinurad doses, 14 and minimal accumulation (~1.2-fold for C max and 1.3-fold for AUC) after QD doses. 14 In a Phase 2a, randomized, double-blind, placebo-controlled trial (NCT03118739), the combination of verinurad + febuxostat lowered sUA and was well tolerated in patients with type 2 diabetes, albuminuria, and hyperuricemia. 15  It is known that the pharmacokinetics of verinurad are dependent on renal function. In a single-dose pharmacokinetics study in participants with varying degrees of renal impairment, verinurad C max increased by 53%, 73%, and 128% and AUC increased by 24%, 148%, and 130% in participants with mild, moderate, and severe renal impairment, respectively, compared with normal renal function. 16 Therefore, it is likely that patients with CKD will have verinurad exposure in the upper range or above what has previously been observed in healthy participants after repeat dosing. In addition, verinurad exposure (C max and AUC) was comparable in healthy Japanese and non-Asian participants when corrected for body weight. 14 Whereas in 2 separate Phase 2 studies in patients with gout -1 Japanese study and 1 Western study -verinurad exposure was >2-fold higher than in Western patients. 17 Therefore, we performed 2 Phase 1 studies which assessed the safety, pharmacokinetics, and pharmacodynamics of verinurad + allopurinol in healthy Asian and Chinese participants (Study 1; NCT03836599) and verinurad monotherapy in healthy non-Asian participants (Study 2; NCT02608710). The specific aims of these studies in healthy participants were to: (1) assess high verinurad exposures with repeat dosing using the same type of formulation as is being used in the Phase 2b CKD and HFpEF studies, and (2) to provide additional data of treatment with verinurad in Asian participants (Study 1) compared with non-Asian participants (Study 2).

| Study design
Study 1 was a randomized, placebo-controlled, Phase 1 study consisting of two cohorts. Cohort 1 was randomized, double-blind, and placebo-controlled and consisted of 12 healthy Asian participants, of whom <50% were Chinese. Cohort 2 was open-label, consisting of 9 healthy Chinese participants. Each cohort underwent a screening period; a 7-day run-in period; a combination treatment period with verinurad + allopurinol for 7 days; and a follow-up visit ( Figure 1). The 7-day run-in period with 300 mg allopurinol was intended to decrease the risk of allopurinol-induced toxicity; allopurinol administration was discontinued if skin rash or signs of allergic reaction appeared. Healthy Asian participants were randomized 3:1 on day -7 to 300 mg allopurinol or placebo QD. In the combination treatment period, participants receiving allopurinol during the run-in period received 24 mg verinurad + 300 mg allopurinol QD during days 1 to 7, and participants receiving placebo continued on placebo. Healthy Chinese participants received 300 mg allopurinol QD during the run-in period. In the combination treatment period, participants received 12 mg verinurad + 300 mg allopurinol QD on day 1, no dosing on day 2, and continued dosing on days 3 to 9. In both studies, participants received verinurad capsules with an extended-release profile. On the days of pharmacokinetic sampling, treatment was given in fasting state. pre-specified study inclusion criteria related to race or ethnicity; however, no Asian participants were enrolled in the study and, therefore, the cohort is referred to as the non-Asian cohort. Key exclusion criteria are listed in the supplemental material.

| Safety evaluation
Analysis of safety was based on adverse events (AEs), laboratory assessments (including hematology, clinical chemistry, urinalysis, and coagulation), vital signs (systolic and diastolic blood pressure, and pulse rate), electrocardiogram (ECG), and physical examination.
AEs were coded using the Medical Dictionary for Regulatory Activities. In Study 1, a treatment-emergent AE was defined as an AE with onset (start date/time) after the first dose of study drug in the run-in period (day -7). In Study 2, AEs were recorded from

| Sample collection and analytical methods
Plasma concentration measurements and serum and urine samples were obtained as described in Supplemental Table S1.
Plasma samples for pharmacokinetic analysis of verinurad, allopurinol, and oxypurinol in Study 1 were analyzed by Covance

| Participants
In Study 1, 22 participants were randomized. Nine healthy Asian participants received allopurinol and 4 received placebo during the run-in period; all but 1 participant completed the run-in period and were randomized to 24 mg verinurad + 300 mg allopurinol (n = 9) or matching placebo (n = 3). Nine healthy Chinese participants received allopurinol during the run-in period and 12 mg verinurad + 300 mg allopurinol in the combination treatment period.
In Study 2, 24 healthy non-Asian participants were randomized.
In the single-dose assessment, 16 participants were randomized to 1 of 6 verinurad treatment sequences ( Figure 1): ABC n = 2, BCA n = 3, CAB n = 3, CBA n = 3, ACB n = 3, BAC n = 2. In the multiple-dose assessment, 8 participants received 12 mg verinurad QD. One participant from the multiple-dose assessment withdrew from the study, after receiving 12 mg verinurad QD on days 1 to 7 as planned.
Baseline demographics and characteristics of participants in both studies are summarized in Table 1.

| Study 2
Two healthy non-Asian participants reported 2 AEs in the single-dose assessment and 2 participants reported 3 AEs in the multiple-dose assessment (Table 3). No AEs occurred in more than 1 participant, with the exception of diarrhea (2 participants; Supplemental  resolving contusion reported at the discharge and follow-up visit in 1 participant, there were no clinically significant findings in physical examinations.

| Study 1
At steady state after 7 days' Q D dosing, the geometric means (gCV%) for C max and AUC τ of verinurad were 73.6 (29.0) ng/mL and 478  Table 4). Plasma concentrations of verinurad showed biphasic decline following C max (Figure 2). Minimal accumulation of verinurad was seen after QD dosing based on R ac C max and R ac AUC τ in healthy Asian (1.03 and 1.15, respectively) and Chinese (0.959 and 1.23, respectively) participants (Table 4).
In both healthy Asian and Chinese participants, plasma Note: Events that emerged during the combination treatment period. AE severity was assessed using the following scale: mild: awareness of sign or symptom, but easily tolerated; moderate: discomfort sufficient to cause interference with normal activities; severe: incapacitating, with inability to perform normal activities.
Abbreviation: AE, adverse event.  Note: AUC, AUC τ , and C max , are geometric mean (gCV%); CL/F and t ½ λz are arithmetic mean (SD); t max is median (range); and R ac AUC τ and R ac C max are geometric mean (range).

TA B L E 3 Study 2: Summary of AEs
Abbreviations: AUC, area under plasma concentration-time curve; AUC τ , AUC over a dosing interval (24 h); CL/F, apparent oral clearance; C max , maximum observed plasma concentration; gCV%, geometric coefficient of variation; R ac , accumulation ratio; SD, standard deviation; t ½ λz, half-life associated with terminal slope of a semi-logarithmic concentration-time curve; t max , time to reach C max . following C max (Supplemental Figure S1). Minimal accumulation of allopurinol was seen after QD dosing based on R ac C max and R ac AUC τ in healthy Asian (1.00 and 0.967, respectively) and Chinese (0.787 and 0.932, respectively) participants (Supplemental Table S4). In both cohorts, the AUC τ and C max of oxypurinol were reduced on the last day of 300 mg allopurinol QD compared with day 1 (Supplemental Table S4).

| Study 2
Following a single dose of verinurad 4.5, 6, or 12 mg, geometric mean C max ranged from 11.8 to 28.6 ng/mL and geometric mean AUC τ ranged from 68.1 to 168 ng·h/mL (Table 5) and appeared to increase dose-proportionally in healthy non-Asian participants. Plasma concentrations of verinurad showed biphasic decline following C max (Figure 2). In the multiple-dose assessment, geometric means (gCV%) for C max and AUC τ of verinurad were 36.3 (36.5) ng/mL and 271 (31.0) ng·hr/mL, respectively, following 12 mg verinurad QD on day 7 ( Table 5). The mean R ac C max and R ac AUC τ values for verinurad on day 7 were 1.21 and 1.30, respectively (Table 5).

| Study 1
Levels of sUA at screening for the 2 cohorts are shown in Table 1.
sUA was reduced from screening after 300 mg allopurinol QD for 7 days, with a mean percentage change on day 1 (pre-dose) of −26.1% in healthy Asian participants and −23.5% in healthy Chinese participants. The combination of 12/24 mg verinurad + 300 mg allopurinol for 7 days further reduced sUA levels compared with day -1 ( Figure 3A). In healthy Asian participants, mean E max,CB of sUA with 24 mg verinurad + 300 mg allopurinol on day 1 was -58.3% and on day 7 was −73.9%, compared with day -1 (Supplemental Table S5).
No clinically meaningful changes in sUA were seen in healthy Asian participants receiving placebo. In healthy Chinese participants, mean E max,CB of sUA with 12 mg verinurad + 300 mg allopurinol on day 1 was −44.9% and on day 9 was −67.2%, compared with day -1 (Supplemental Table S5).
In the single-dose assessment, mean Ae ur assessed over 24 h post-dose increased dose-proportionally. Mean Ae ur peaked at 3 to 6 h post-dose; mean Ae ur following 4.5, 6, and 12 mg verinurad was 219%, 267%, and 338% higher, respectively, compared with day -1 (Supplemental Figure S3A). In the multiple-dose assessment, mean Ae ur peaked 3 to 6 h post-dose following 12 mg verinurad QD on days 1 and 7; mean Ae ur was 353% and 81.3% higher, respectively, compared with day -1 (Supplemental Figure S3B).

F I G U R E 3 Study 1: Mean (SD) observed (A) sUA and (B) FEUA in healthy Asian and Chinese participants. Healthy Asian participants:
24 mg verinurad + 300 mg allopurinol or matching placebo once daily for 7 days. Healthy Chinese participants: 12 mg verinurad + 300 mg allopurinol on day 1 and then once daily on days 3-9. Baseline (day -1) represents sUA and FEUA following 7 days of 300 mg allopurinol during the run-in period. In healthy Asian participants, sUA levels at screening (day -8) and baseline (day -1), respectively, were 6.31 mg/ dL and 4.77 mg/dL with 24 mg verinurad + 300 mg allopurinol and 7.40 mg/dL and 6.97 mg/dL with matching placebo. In healthy Chinese participants, sUA levels at screening (day -8) and baseline (day -1), respectively, were 5.64 mg/dL and 4.49 mg/dL with 12 mg verinurad + 300 mg allopurinol. Abbreviations: FEUA, fractional excretion of uric acid; SD, standard deviation; sUA, serum uric acid with an increased C max of 73% and 128% and an increased AUC of 148% and 130% in participants with moderate and severe renal impairment, respectively, compared with normal renal function. 16 Given the potential for higher verinurad exposure in the target patient population, i.e. those with reduced renal function, 16  When accounting for differences in dose, the steady-state exposure of verinurad following QD dosing for 7 days was generally comparable between healthy Asian and Chinese participants (Study 1) and between healthy Asian and non-Asian participants (Study 2).
Accordingly, these findings suggest that Asian ethnicity does not impact verinurad pharmacokinetics.
Data from Study 2 (4.5-12 mg verinurad) and Study 1 (12 and 24 mg verinurad) support that verinurad exposure increases dose-proportionally in the studied dose range, with minimal accumulation following multiple QD dosing, as seen previously with verinurad among healthy Japanese participants. 14 In Study 1, comparison of day 1 and day 7/9 data suggests that verinurad co-administration did not influence the exposure of allopurinol, which is consistent with the results from a drug-drug interaction study with verinurad and allopurinol among patients with gout; 18 this study also showed that allopurinol does not influence the pharmacokinetics of verinurad. 18 Oxypurinol exposure was lower on day 7/9 compared with day 1, which is to be expected following several days of co-administration with verinurad. 18 In both studies, healthy participants had baseline sUA levels Study 2) and differences in scales used to assess AE severity.
Phase 2 studies evaluating verinurad combined with 300 mg allopurinol are currently ongoing in patients with CKD and HFpEF.
Studies 1 and 2 allowed the evaluation of verinurad at exposures expected to be seen in patients with impaired renal function after dosing of the highest dose currently being tested in Phase 2.

ACK N OWLED G M ENTS
The authors thank the study participants. We also thank Alex Yao for her scientific contribution to the study. Medical writing support was

S TU DY PR I N CI PA L I N V E S TI G ATO R S TATE M E NT
The authors confirm that the PIs for this paper are Drs David Han and Thomas Hunt and that they had direct clinical responsibility for patients.

PATI ENT CO N S ENT S TATEM ENT
All participants provided written informed consent.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astra zenec agrou p-dt.pharm acm.com/DT/Home.